Increlex (mecasermin)

Mecasermin, a somatotropin agonist (a somatomedin), is a biosynthetic (recombinant DNA origin) form of human insulin-like growth factor I (IGF-1; IGF-I).

Mecasermin is a biosynthetic (recombinant DNA origin) form of human insulin-like growth factor I (IGF-I), the principal mediator of the somatotropic effects of human growth hormone (GH; somatropin).

Growth hormone binds to GH receptors in the liver and other tissues and stimulates the synthesis of IGF-I. In target tissues, IGF-I activates the IGF-I receptor, leading to intracellular signals that stimulate growth. Although many of the actions of GH are mediated through IGF-I, the precise roles of GH and IGF-I have not been fully elucidated.

IGF-I has been shown to stimulate mitogenesis in many tissues. Endogenous or exogenously administered IGF-I promotes linear growth by stimulating proliferation of chondrocytes in the epiphyseal cartilage, proliferation of osteoblasts, and formation of soft connective tissue (as evidenced by increased production of procollagen). In patients with IGF-I deficiency, exogenously administered IGF-I promotes the growth of various organs, including the spleen, kidneys, and lymphoid tissues.

Because IGF-I is structurally similar to insulin, IGF-I binds with low affinity to the insulin receptor and affects carbohydrate metabolism by suppressing hepatic glucose production and stimulating peripheral glucose utilization. Hypoglycemia may occur, particularly during the first month of treatment. However, during long-term administration, exogenous IGF-I suppresses insulin secretion.

Following subcutaneous administration of mecasermin in healthy individuals, bioavailability is approximately 100%. Bioavailability in individuals with IGF-I deficiency has not been determined. In individuals with severe IGF-I deficiency, serum concentrations of IGF-I were very low prior to mecasermin administration.

Following administration of a single dose (0.12 mg/kg) of the drug in these individuals, average peak plasma concentrations attained at 2 hours were below normal or in the low-normal range. Tissue availability of free IGF-I is determined by the presence of 6 IGF binding proteins (IGFBPs) in the blood. These IGFBPs, particularly IGFBP-3, limit the extent of distribution.

It is not known whether mecasermin is distributed into milk. At least 99% of circulating IGF-I is bound to IGFBPs, with at least 80% bound as a complex with IGFBP-3 and an acid labile subunit. Plasma concentrations of IGFBP-3 and acid labile subunit are reduced in patients with severe primary IGF deficiency compared with healthy individuals, resulting in greater drug clearance.

Mecasermin and endogenous IGF-I are metabolized by lysosomal enzymes principally in the liver and kidneys to amino acids. Mecasermin is excreted principally in urine. Presumably less than 0.1% is excreted in urine as unchanged drug based on studies with endogenous IGF-I.

The terminal half-life of mecasermin averages 5.8 hours in children with severe primary IGF deficiency and 19.2 hours in healthy individuals. The pharmacokinetics of mecasermin are unaffected by gender. The effect of race on pharmacokinetics of mecasermin has not been established.

Generic name: mecasermin
Drug class: Insulin-like Growth Factor-1 (IGF-1) agents
Therapeutic class: Endocrine

The following indications are listed for Increlex:

• Primary Insulin-Like Growth Factor-1 Deficiency

Also known as: Pituitary Dwarfism With Normal Somatotropin And Low Somatomedin, Primary Igf-1 Deficiency, Primary Insulin-Like Growth Factor Deficiency.